This is a four year mentored training program under the direction of Dr. Kim Bottomly, Professor of Immunobiology at Yale School of Medicine. After completing a residency in Dermatology at Yale, I joined Dr. Bottomly's lab as a postdoctoral fellow, studying Th2-mediated lung inflammation in a mouse model of Asthma. My interest in this project was a natural outgrowth of my doctoral studies involving regulation of IgE responses and my clinical interest in atopic dermatitis. I established a novel method of inducing strongly biased Th2 responses in vivo by epicutaneously (e.c.) exposing mice to soluble protein. Upon airway challenge, these e.c. sensitized mice develop lung inflammatory responses with features of human allergic asthma, including high numbers of eosinophils and mucus hypersecretion. We have shown that: 1) these e.c.- induced Th2 responses are IL-4 independent, but STAT6 dependent; 2) IL-4 independent Th2 responses in e.c. sensitized C57BL/6 mice are dependent on IL- 13; and 3) eosinophil migration from lung into airway in e.c. sensitized mice is IL-4 dependent in BALB/c, but not in C57BL/6, mice. It is our hypothesis that recruitment of eosinophils to the airway of e.c. sensitized mice is differentially regulated in these two strains because of differences in IL-13 production or receptivity. This will be tested in the following specific aims: 1) definition of the role of IL-13 during e.c. sensitization in BALB/c and C57BL/6 mice; and 2) determination of the cellular, molecular, and genetic factors that regulate airway eosinophilia in e.c. sensitized mice. In the third specific aim, the mechanisms put forth to explain the genetic difference in regulation of Th2 lung inflammation will be extended to the skin. This will involve establishing a new model of Th2-mediated skin inflammation by secondary antigen challenge in the skin (rather than the airway) of e.c. sensitized mice. Questions to be answered in this aim include: 1) is cutaneous inflammation governed by the same factors operating in the lung? 2) is eosinophil recruitment to skin IL-4 dependent in BALB/c mice, but not in C57BL/6 mice?; and 3) what is the role of IL-13 in skin inflammation? My plan is to continue working with Dr. Bottomly over the next several years to answer these questions. During this time, establishment of a novel model of Th2- mediated skin inflammation will provide me with a unique system in which to pursue future inquiries, facilitating my transition to an independent investigator. My goal is to continue basic science investigation of atopic skin disease as a junior faculty member in the Department of Dermatology at Yale School of Medicine.